Health Effects of Diisocyanates: Guidance for Medical Personnel

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4 Center for the Polyurethanes Industry Carefully controlled specific provocative inhalation tests with diisocyanates may be used, but are usually not readily available. Such bronchial provocation testing uses elaborate exposure equipment and experienced technicians. Confirming work-related bronchoconstriction by demonstrating decrement of lung function in association with workplace exposures is usually sufficient to confirm or contradict the presumptive diagnosis. Immune testing, including diisocyanate-specific IgE and IgG testing in blood serum, has not been standardized and validated and as a consequence has not shown adequate specificity and sensitivity for diagnosis (Budnik, 2012). ALVEOLITIS OR HYPERSENSITIVITY PNEUMONITIS On occasion, alveolitis or hypersensitivity pneumonitis, may result from diisocyanate exposure. In contrast to bronchial asthma, alveolitis has been reported in isolated case reports usually when there have been gross overexposures. Symptoms may appear 6 to 8 hours after exposure and may include malaise, joint pain, fever, cough, and shortness of breath. Chest X-rays may show “shadows” on the lungs. The condition usually subsides upon removal from exposure. Diagnosis of the condition requires the following criteria: clinical (a flu-like syndrome) with fever and shortness of breath, radiographic (lung infiltrates), physiologic (restrictive pattern in lung function) and immunologic (presence of specific IgG antibodies) (Baur, 1995). Other investigators have not found the IgG antibodies in all cases and concluded that the clinical syndrome in the presence of non-irritating concentrations of diisocyanates as a sensitive indicator of the disease (Vandenplas, 1993). Signs and symptoms usually disappear in a few days upon removal from exposure. However, if exposure is continued, chronic lung fibrosis, impaired gas exchange, labored breathing, and reduced physical fitness may develop. SKIN EFFECTS DERMAL IRRITATION Repeated contact with liquid diisocyanates may discolor the skin or cause signs of irritation such as redness, irritation, swelling, and/or blistering. If diisocyanates accidentally come in contact with the skin, wash immediately with soap and water. Cured material is difficult to remove; however, practical experience has demonstrated that some of the best ways to remove it is with corn oil, petroleum jelly or industrial skin cleansers (e.g., D-TAM TM Safe Solvent: Colorimetric Laboratories, Inc.). ALLERGIC CONTACT DERMATITIS Dermal exposure to diisocyanates may also result in allergic contact dermatitis (ACD). ACD is a rare occurrence with MDI and TDI. ACD is a two-step process: the first phase is induction of specialized immunological memory in an individual by exposure to an allergen; the second phase is elicitation -- the production of a cell-mediated allergic response by re-exposure of a sensitized individual to an allergen. Persons previously sensitized can experience allergic skin reaction with the symptoms of reddening, itching, swelling, and rash upon dermal contact.
Evidence in animal studies suggests that repeated dermal exposure may also play a role in the development of respiratory sensitization. Both TDI and MDI have induced respiratory hypersensitivity responses when applied to, or injected into, the skin of animals and followed by inhalation exposure. Based on these findings, it is strongly recommended that skin contact with diisocyanates be avoided. CARCINOGENICITY For hazard communication purposes under OSHA Standard 29 CFR, Part 1910.1200, TDI is listed as a potential carcinogen by the National Toxicology Program (NTP) and the International Agency for Research on Cancer (IARC). Both agencies based their evaluation of TDI as a potential carcinogen primarily on an oral study in which high doses of TDI were reported to cause cancer in animals. This study, in which rats and mice were administered high doses of TDI in corn oil by oral gavage, has been found to contain deficiencies that resulted in the formation of toluene diamine (TDA), a known animal carcinogen. TDI did not cause cancer or result in the formation of detectable levels of free TDA when laboratory animals were exposed by inhalation, by far the most likely route of exposure (Loser, 1983). A study to determine the chronic toxicity and potential carcinogenicity of MDI has been conducted. Male and female rats were exposed 6 hours/day, 5 days/week for two years to an atmosphere of respirable polymeric MDI aerosols at concentrations of 0.2 mg/m 3 , 1.0 mg/m 3 , or 6.0 mg/m 3 (Reuzel et al., 1994). A low incidence of primarily benign lung tumors in Type II cells were seen at only the highest concentration. In a second study (Hoymann et al., 1995), female rats were exposed 17 hours/day, 5 days/week for 2 years to an atmosphere of respirable monomeric MDI aerosols at concentrations of 0.23 mg/m 3 , 0.70 mg/m 3 or 2.03 mg/m 3 . A benign lung tumor was only observed in a single rat at 2.03 mg/m 3 . Several in vitro studies used solvents that cause rapid hydrolysis of TDI to its diamine, a known mutagen, and the results have been discounted (Herbold et al., 1998; Seel et al., 1999). A weight of evidence assessment of in vitro and in vitro testing indicates that TDI has no mutagenic activity. Numerous in vitro mutagenicity studies have been done on MDI that do not show a mutagenic potential, except under conditions using solvents which cause rapid hydrolysis of MDI to its diamine, a known mutagen (Herbold et al., 1998; Seel et al., 1999). This may account for the mutagenic findings. The majority of the studies using a different solvent have not resulted in mutagenicity. The results of these studies suggest that the incidence and delayed occurrence of lung tumors is consistent with a nongenotoxic mode of action since MDI-DNA adducts are not detected in organs with tumors or at doses associated with cell proliferation. Since lung tumors only were observed at a concentration orders of magnitude higher than established occupational exposure guidelines, MDI is unlikely to pose a significant cancer risk to workers. Several epidemiology studies were unable to show a significant link between employment in polyurethane manufacturing and cancer deaths: • 40-year cohort study of TDI polyurethane foam manufacturing in England and Wales (Sorahan and Pope, 1993; Sorahan and Nichols, 2002) • 37-year cohort study of TDI polyurethane foam manufacturing in US (Schnorr et al., 1996) • 29-year cohort study of TDI and MDI polyurethane foam manufacturing in Sweden (Hagmar et al., 1993a; Hagmar et al., 1993b) • 40-year cohort study of TDI and MDI. Follow-up of the Hagmar et al. studies in Sweden (Mikoczy et al., 2004) Center for the Polyurethanes Industry 5
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Health Effects of Diisocyanates: Guidance for Medical Personnel

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